Lysophosphatidic acid (LPA) and its receptor, LPA₁, influence embryonic schwann cell migration, myelination, and cell-to-axon segregation

Abstract

Schwann cell (SC) migration is an important step preceding myelination and remyelination in the peripheral nervous system, and can be promoted by peptide factors like neuregulins. Here we present evidence that a lipid factor, lysophosphatidic acid (LPA), influences both SC migration and peripheral myelination through its cognate G protein-coupled receptor (GPCR) known as LPA1. Ultrastructural analyses of peripheral nerves in mouse null-mutants for LPA1 showed delayed SC-to-axon segregation, polyaxonal myelination by single SCs, and thinner myelin sheaths. In primary cultures, LPA promoted SC migration through LPA1, while analysis of conditioned media from purified dorsal root ganglia neurons using HPLC/MS supported the production of LPA by these neurons. The heterotrimeric G-alpha protein, Gαi, and the small GTPase, Rac1, were identified as important downstream signaling components of LPA1. These results identify receptor mediated LPA signaling between neurons and SCs that promote SC migration and contribute to the normal development of peripheral nerves through effects on SC-axon segregation and myelination.

Lysophosphatidic acid signalling in development

“…Moreover, in zebrafish, enpp2 regulates the commitment of olig2-expressing progenitors into lineage committed oligodendrocyte progenitors, supporting the role for LPA in this process (Yuelling et al, 2012). In the mouse peripheral nervous system, Schwann cells depend upon LPA signalling for both survival (Contos et al, 2000;Weiner and Chun, 1999) and proper myelination (Anliker et al, 2013;Weiner et al, 2001), and they express Lpar1, Lpar4 and Lpar6 (Anliker et al, 2013). Microglia are the resident macrophages of the CNS and have developmental roles (Innocenti et al, 1983).…”

“…LPA signalling influences the survival, proliferation, differentiation, migration, adhesion and morphology of a range of cell types during development. These include neural progenitor cells (NPCs), astrocytes and oligodendrocytes in the nervous system (Anliker et al, 2013;Fukushima et al, 2002), endothelial cells during vascular formation and maintenance (Chen et al, 2013;Yukiura et al, 2011), cells of the reproductive system (Ye and Chun, 2010), osteoblasts and osteoclasts during bone development (Lapierre et al, 2010;Liu et al, 2010), proliferating pre-adipocytes (Valet et al, 1998), and cells of the immune system (Chan et al, 2007;Goetzl et al, 2000;Zhang et al, 2012). Here, we review how LPA is produced and metabolised during development, how it signals and how it influences the development of a number of tissues and organs.…”

Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex

“…Peripherally, a recent study has showed the involvement of the LPA 1 receptor in Schwann cell migration and nerve development, including myelination, in sciatic nerves (Anliker et al 2013). Notwithstanding these studies, the function of LPA 1 receptor in brain myelination remains to be demonstrated.…”

G Protein-Coupled Receptors in Myelinating Glia

“…The LPA1 ligand, lysophosphatidic acid (LPA), is produced by neurons and is a potent survival and migration factor for Schwann cells in culture [40,41]. Analysis of Lpa1 knockout mice demonstrate that this receptor is required for Schwann cell survival, radial sorting, and proper myelination in vivo [40,41].…”

“…The LPA1 ligand, lysophosphatidic acid (LPA), is produced by neurons and is a potent survival and migration factor for Schwann cells in culture [40,41]. Analysis of Lpa1 knockout mice demonstrate that this receptor is required for Schwann cell survival, radial sorting, and proper myelination in vivo [40,41]. The role of axon-Schwann cell GPCR signaling in controlling radial sorting also likely extends to other players, given that neuronally-derived Wnt and Respondins may also signal via Lgr receptors and Lrp/Frizzled receptor complexes on Schwann cells [42].…”